Agilus

Package leaflet: Information for the user

Agilus 120 mg powder for injectable solution

dantrolene sodium hemiheptahydrate
Please read this leaflet carefully because it contains important information for you.
This medicine is used in emergency situations and its use must have been determined necessary by the doctor.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor.
• If you experience any side effects, including those not listed in this leaflet, consult your doctor. See section 4.

Contents of this leaflet

1. What Agilus is and what it is used for
2. What you need to know before being administered Agilus
3. How Agilus is administered
4. Possible side effects
5. How to store Agilus
6. Contents of the pack and other information

1. What Agilus is and what it is used for

Agilus contains dantrolene sodium. It is a type of medicine called a direct-acting muscle relaxant.
It binds to a target within muscle cells and helps the body's muscles to relax when they are overstimulated.
Together with other supportive measures, this medicine is used to treat malignant hyperthermia in adults and children of all ages. Malignant hyperthermia is a life-threatening emergency condition in which the body's skeletal muscles are overstimulated and unable to relax. This can cause a very rapid increase in body temperature and/or a build-up of waste products in the body (metabolic acidosis), which may prevent vital organs from functioning properly.

2. What you should know before being given Agilus

Do not take Agilus

• if you are allergic to dantrolene sodium or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
You have probably already been given this medicine before reading this leaflet.
Contact your doctor or nurse if:

• you are currently taking medicines for high blood pressure or angina called “calcium channel blockers”. Taking these medicines together with Agilus may increase the amount of potassium in your blood, which could cause irregular heart rhythms or inability to move certain muscles.
• you think some of the medicine has spilled onto your skin, it should be removed by washing with water.

Liver damage has been observed in patients exposed to long-term oral use of dantrolene sodium. Inform your doctor if you think you may have symptoms of liver damage (e.g. if your skin or eyes appear yellowish, or if you experience abdominal pain and swelling).

Other medicines and Agilus
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
The following medicines may affect how Agilus works, or Agilus may affect how these medicines work:

• medicines for high blood pressure and angina called “calcium channel blockers”, such as verapamil or diltiazem, may cause heart failure if administered together with Agilus. (See Warnings and precautions).
• muscle relaxants, such as vecuronium, may enhance the muscle-relaxing effect of Agilus if administered at the same time.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breastfeeding, consult your doctor or nurse, if possible, before being given this medicine.

Pregnancy
Agilus will not be used during pregnancy unless considered necessary. After receiving Agilus, the muscles of your uterus may become weak. If you receive Agilus during a caesarean section, the newborn may develop muscle weakness.

Breastfeeding
Do not breastfeed while taking Agilus or for 60 hours after the last dose. Inform your doctor if you are breastfeeding.

Driving and using machines
After being given Agilus, the muscles in your arms and legs may be weak, and you may also feel dizzy or lightheaded. These effects may last up to 48 hours after administration of Agilus. Do not drive or operate machinery during this period.

Agilus contains cyclodextrin and sodium
This medicine contains 3,530 mg of hydroxypropyl betadex (a cyclodextrin) in each vial, equivalent to 156.2 mg/mL in the reconstituted solution.
Inform your doctor if you have previously had hearing problems, for example, if you are prone to ear infections. Cases of hearing disorders have been observed in patients who have received hydroxypropyl betadex for other conditions, at doses higher than those recommended for Agilus. These hearing disorders are generally mild and temporary. For patients requiring high doses of Agilus (greater than 10 mg/kg), treatment will be re-evaluated due to this risk.
The potential risk associated with hydroxypropyl betadex may increase if your kidneys are not functioning properly.

This medicine contains 6.9 mg of sodium (a main component of table salt) in each vial. This is less than 0.5% of the maximum daily intake recommended in an adult diet.

3. How Agilus is administered

This injection will be given to you intravenously by a healthcare professional. The dose of Agilus you receive depends on your body weight. The dose will be repeated every 10 minutes until your symptoms improve. If your symptoms do not improve after taking the medicine, your doctor may reconsider the diagnosis and consider alternative treatments. If a relapse occurs, the healthcare professional will administer Agilus to you again.

If you have been given too much Agilus

If you have received more Agilus than you should have, side effects may occur. Severe muscle weakness may develop, which could affect your breathing. Your doctor will monitor you closely.

If you have any doubts about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects have been observed with the active substance in Agilus.
The frequency of the following side effects is not known (frequency cannot be estimated from the available data).
Serious side effects: your doctor will immediately stop treatment with Agilus

• severe, sudden allergic reaction with breathing difficulties, swelling, dizziness, rapid heartbeat, sweating, and loss of consciousness (anaphylactic reaction)

Other side effects
The following side effects have been observed with the active substance in Agilus:

• allergic reactions (hypersensitivity)
• high levels of potassium in the blood (hyperkalaemia), which may cause tiredness, muscle weakness, feeling unwell, and irregular heart rhythm
• dizziness, drowsiness, seizures, difficulty speaking (dysarthria), headache
• altered vision
• heart failure, slow heartbeat (bradycardia), fast heartbeat (tachycardia)
• inflammation in a vein causing a blood clot and blockage (thrombophlebitis)
• breathing difficulties (respiratory failure), breathing that is too slow and shallow (respiratory depression)
• stomach pain (abdominal pain), nausea (feeling unwell), vomiting, bleeding in the intestine and stomach with symptoms such as blood in stools or vomit (gastrointestinal haemorrhage), diarrhoea, difficulty swallowing (dysphagia)
• yellowing of the eyes and skin (jaundice), inflammation of the liver (hepatitis), liver failure which may be fatal, changes in blood tests relating to liver function, liver disease due to unknown cause or allergic reaction
• itchy skin rash (urticaria), redness of the skin (erythema), excessive sweating (hyperhidrosis)
• muscle weakness, muscle fatigue
• presence of crystal particles in the urine (crystalluria)
• weak contractions during childbirth (uterine hypotonia)
• feeling of tiredness (fatigue), general weakness (asthenia), reactions at the injection site

These side effects have been observed in situations where treatment with dantrolene was administered orally for a prolonged period.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system referred to in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Agilus

Keep this medicine out of the sight and reach of children.
This medicine will be stored in a hospital setting and these instructions are intended for healthcare professionals only.
Unopened vial: no special storage temperature requirements. Store the vial in the original packaging to protect it from light.
Reconstituted solution: use within 24 hours. The reconstituted solution must be protected from light.
Do not store above 25 °C and do not refrigerate.
Do not use this medicine after the expiry date stated on the label and outer carton of the vials after "Exp.". The expiry date refers to the last day of that month.
For single use only. Discard any remaining reconstituted solution.

6. Package contents and other information

What Agilus contains
The active substance is dantrolene sodium hemiheptahydrate.
One vial contains 120 mg of dantrolene sodium hemiheptahydrate. After reconstitution with 20 mL
of water for injections, each millilitre of solution contains 5.3 mg of dantrolene sodium hemiheptahydrate.
The other components are hydroxypropyl betadex (a cyclodextrin) and macrogol (E1521). See
section 2 “Agilus contains cyclodextrin and sodium”.
Description of the appearance of Agilus and contents of the pack
Glass vials with rubber stopper and seal, containing 120 mg of yellow-orange powder for injectable solution.
Pack sizes of 6 or 10 vials.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and manufacturer
Norgine B.V.
Antonio Vivaldistraat 150
1083 HP Amsterdam
The Netherlands
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu .
This leaflet is available in all languages of the European Union/European Economic Area on the
website of the European Medicines Agency.

The following information is intended exclusively for healthcare professionals:

Posology and method of administration
Treatment with Agilus should be initiated as soon as malignant hyperthermia is suspected,
which typically presents with muscle rigidity, metabolic acidosis and/or rapidly rising body temperature.

Posology
Agilus must be administered rapidly by intravenous injection at an initial dose of 2.5 mg/kg body weight in both adult and pediatric patients.

As long as the main clinical symptoms of tachycardia, hypoventilation, prolonged acidosis (monitoring of pH and partial pressure of carbon dioxide (pCO₂) is required), and hyperthermia persist, repeated bolus injections of 2.5 mg/kg should be administered every 10 minutes until physiological and metabolic abnormalities improve. If a cumulative dose equal to or greater than 10 mg/kg is being considered, the diagnosis of malignant hyperthermia should be reconsidered.

The following table provides dosage examples based on the number of vials required for the initial 2.5 mg/kg dose, to be administered immediately by rapid injection:

Table 1: Dosage examples

Treatment of recurrence (relapse)
It should be noted that the hypermetabolic features of malignant hyperthermia may recur within the first 24 hours after initial resolution. If recurrence occurs, administer Agilus again at a dose of 2.5 mg/kg every 10 minutes until signs of malignant hyperthermia subside once more. The same considerations regarding monitoring of metabolic abnormalities and dose titration in an initial episode apply to the treatment of recurrence.

Paediatric population
No dose adjustment is required.

Method of administration
For intravenous use.

Special precautions for storage, preparation and handling
Preparation
Each vial must be reconstituted by adding 20 mL of water for injections and shaking for approximately 1 minute, before checking for particulate matter. Further shaking may be necessary. The reconstituted solution must be yellow-orange in colour and free from particles. The volume of solution in a reconstituted vial is 22.6 mL.

Chemical and physical in-use stability has been demonstrated for 24 hours at 25 °C. From a microbiological standpoint, unless the method of opening/reconstitution excludes the risk of microbial contamination, the reconstituted product should be used immediately. If not used immediately, the user is responsible for the storage times and conditions during use, which must not exceed 24 hours at 25 °C.

Storage
The unopened vial does not require any specific storage temperature. Store the vial in the outer packaging to protect it from light.

The reconstituted solution must be protected from light. Do not store above 25 °C and do not refrigerate.

Handling
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. The reconstituted solution of Agilus must not be mixed with other solutions or administered through the same intravenous line.

Avoid spilling the solution onto the skin. If contact with the skin occurs, wash thoroughly with ample water.

This medicinal product is for single use only, and any remaining reconstituted solution must be discarded.

Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.